Prostate Cancer Survival Metrics: A New Standard?
Effective clinical trial design and ultimately drug approval require careful consideration of the endpoints selected.
The debate over which clinical endpoints best measure the efficacy of a cancer intervention persists. Value is in the eye of the beholder. For patients with advanced malignancies, improving overall survival (OS) remains the “holy grail,” the gold standard in most randomized clinical trials. Either a drug statistically extends your life or it does not.
Critics justifiably have argued that OS is not the only important measure of the success of a pharmacologic intervention. Other primary and secondary endpoints include progression- free survival (PFS), disease-free survival (DFS), metastasisfree survival (MFS), overall response rates (ORR), complete durable responses, patient reported outcomes, and other surrogate (often biomarker) endpoints. Effective clinical trial design and ultimately drug approval require careful consideration of the endpoints selected, and, increasingly, a dialogue with investigators and regulatory agencies regarding their willingness to accept survival endpoints short of OS.
In prostate cancer (PCa), this debate is particularly sharp, whereas the natural history of advanced PCa often extends for years. Therefore, a patient who progresses to castration-resistant disease may be exposed to multiple treatments over several years prior to his death. As novel, sequential and combination therapies improve longevity, measuring the effects on OS by a medication tested years earlier becomes incrementally problematic.
The FDA approval of apalutamide on February 14, 2018 for patients with non-metastatic castrate-resistant prostate cancer (nmCRPC) reflects the agency's growing awareness that clinically meaningful cancer endpoints exist in PCa short of OS.1 Approval was based on the results of the SPARTAN trial (NCT01946204), which randomized 1,207 patients with nmCRPC (2:1) to receive either apalutamide, an oral non-steroidal antiandrogen, or placebo in combination with ADT. MFS (time from randomization to first evidence of distant metastasis or death) was 40.5 months for apalutamide vs 16.2 months for placebo (hazard ratio 0.28; 95% CI: 0.23, 0.35; p<0.0001).2 While OS data are not yet mature, there are tantalizing hints that MFS may be a good surrogate for OS. Moreover, living metastasis free for an additional 2+ years may not only decrease the risks of skeletal-related events such as pathologic fractures, but likely provides a measurable psychological boost to patients.
These debates bring us back to the concept of value in health care. That requires a conversation between multiple stakeholders. It should be recognized that the FDA is increasingly listening.